Serum Hepatitis C Virus RNA Levels Research Articles

The Efficacy of Short-Term Interferon-Beta Therapy for Type C Cirrhotic Patients with Genotype 2a and Low Virus Load

The aim of this study was to elucidate the efficacy of short-term interferon (IFN) therapy for type C cirrhotic patients with genotype 2a and low virus load. The present study was retrospective cohort study. Inclusion criteria were liver cirrhosis, hepatitis C virus (HCV) genotype 2a, the serum HCV RNA level of less than 100 KIU/mL, and IFN period of 6 or 8 weeks. Twenty-five consecutive patients who satisfied the above criteria were treated with IFN-beta daily at the dosage of 6 MU for 6 or 8 weeks. Independent factors that might have influenced sustained virologic response (SVR) were studied using multiple logistic regression analysis. Background of clinical profiles were as follows: median (range) age=64 (53-76) years, male/female=13/12, and median (range) HCV-RNA=31 (8-90) KIU/mL. Out of 25, 14 patients (56.0%) had SVR by the intention-to-treat analysis. The SVR was significantly associated with serum HCV RNA level. Logistic analysis showed that SVR occurred when HCV RNA level was <50 KIU/mL (p=0.047). Based on the difference of the serum HCV RNA level, the SVR rate was 68.4% (13/19) in patients with a serum HCV RNA level of <50 KIU/mL and 16.7% (1/6) in patients with a serum HCV RNA level of > or =50 KIU/mL. The 6 or 8-week IFN-beta therapy is a possible selection of therapy for cirrhotic patients with HCV genotype 2a and a serum HCV RNA level of <50 KIU/mL.

Efficacy in Patients with Dose Reduction in Combination Therapy of Peginterferon and Ribavirin for Chronic Hepatitis C

Objective: The aim of this study was to elucidate efficacy after dose reduction in combination therapy of peginterferon and ribavirin for chronic hepatitis C. Methods: Inclusion criteria were hepatitis C virus (HCV) genotype 1b, serum HCV RNA level of ≧100 KIU/ml, dose reduction of peginterferon and/or ribavirin between the first 4 weeks and 20 weeks after the initiation of treatment. 164 patients were enrolled in this retrospective cohort study. Predictive factors for sustained viral response (SVR) after dose reduction were examined. Results: Out of the 146 patients treated with dose reduction, 57 had SVR. Multivariate analysis showed that SVR occurred when serum HCV RNA at the time of dose reduction was negative (p < 0.001) and total ribavirin dose was ≧100% of the anticipated total dose (p < 0.001). 57% (55/97) of patients with undetectable serum HCV RNA at the time of dose reduction had SVR. In contrast, only 4% (2/49) of patients with detectable serum HCV RNA at the time of dose reduction had SVR. Conclusions: On dose reduction of combination therapy for chronic hepatitis C, undetectable serum HCV RNA at the time of dose reduction and attainment of the total ribavirin dose of ≧100% enhance SVR.

Insulin Resistance in Chronic Hepatitis C: Association With Genotypes 1 and 4, Serum HCV RNA Level, and Liver Fibrosis

Our study was designed to test the association between insulin resistance (IR) and hepatitis C virus (HCV) genotypes, serum HCV RNA level and liver fibrosis stage in a large prospective cohort of chronic hepatitis C (CHC) patients. Six hundred consecutive patients (CHC, n = 500; chronic hepatitis B (CHB), n = 100) were evaluated on the day of liver biopsy. IR (Homeostasis Model for Assessment of Insulin Resistance) and all components of the metabolic syndrome were assessed. By logistic regression, independent factors associated with IR and those associated with significant fibrosis were assessed in nondiabetic and noncirrhotic CHC, respectively. Parameters of IR were compared between hepatitis B and 240 CHC matched by epidemiologic, metabolic, and histologic features. IR was present in 32.4% of the 462 nondiabetic CHC and associated with the metabolic syndrome, genotypes 1 and 4, significant fibrosis, and severe steatosis. IR was diagnosed in 15% of 145 CHC without metabolic syndrome or significant fibrosis, and associated with genotypes 1 and 4, high serum HCV RNA level, and moderate-severe necroinflammation. Significant fibrosis was present in 51.1% of the 454 noncirrhotic CHC patients and associated with male sex, age >40 years, IR, moderate-severe necroinflammation, and severe steatosis. IR was less frequent in CHB than in matched CHC (5% vs 35%, respectively, P < .001). IR is a specific feature of CHC, associated with genotypes 1 and 4 and high serum HCV RNA level. Significant fibrosis is associated with IR independent from steatosis.

To Investigate the Utility of a Week-4 Virological Response for SVR Prediction in Hepatitis C Virus (HCV) Genotype 3 Patients Treated with Pegylated Interferon and Ribavirin for 24 Weeks

Purpose: To investigate the utility of a week-4 virological response for SVR prediction in hepatitis C virus (HCV) genotype 3 patients treated with Pegylated interferon and ribavirin for 24 weeks. Methods: Using a PCR-based quantitative assay we analysed samples obtained at baseline and weeks 4 and 12 from a subset of 50 HCV genotype 3 patients enrolled in a randomized trial of peginterferon a-2a in combination with ribavirin. Results: In an intention-to-treat analysis, 84% of patients treated with peginterferon achieved a sustained virological response (SVR). At 4 weeks, 50% of patients had HCV RNA < 50 IU/ml and 65% had < 600 IU/ml. Of these rapid responders 86 and 87% achieved a SVR, respectively, with 2 patients relapsing. In contrast, only 44 and 31% of patients with a week-4 HCV RNA < 50 or < 600 IU/ml achieved an SVR, respectively, with relapse rates of 23 and 55%, respectively. In multivariate logistic regression analysis a serum HCV RNA level below 600 IU/ml at week 4 was the strongest independent predictor of SVR (odds ratio, 11.5; 95% confidence interval, 1.5 to 65.0; P= 0.015). Conclusion: Monitoring early viral response may be useful to tailor the duration of treatment among patients with HCV genotype 3. Patients whose HCV RNA falls below 600 IU/ml at 4 weeks are at low risk of relapse after 24 weeks of combination therapy.

Baseline Serum Hepatitis C Virus (HCV) RNA Level and Response at Week 4 Are the Best Predictors of Relapse After Treatment With Pegylated Interferon Plus Ribavirin in HIV/HCV-Coinfected Patients

Relapse after achieving virologic response to anti-hepatitis C virus (HCV) treatment considerably reduces sustained virologic response rates. It is unclear what the main predictors of relapse in HCV/HIV-coinfected patients are. The Pegasys Ribavirina España Coinfección (PRESCO) study evaluated short and extended duration of treatment for chronic hepatitis C using pegylated interferon (peg-IFN)-alpha2a at a dose of 180 microg/wk plus weight-based ribavirin (RBV) at a dose of 1000 to 1200 mg/d in HIV-infected subjects. Patients with HCV-2/3 were treated for 6 or 12 months, and patients with HCV-1/4 were treated for 12 or 18 months. Of 389 patients included in the trial, end-of-treatment response was achieved by 262 (67.3%): 106 with HCV-1 (55%), 137 with HCV-2/3 (90%), and 19 with HCV-4 (41%). Six patients were lost to follow-up after completing therapy. Of the remaining 256 patients, 62 (24%) relapsed: 33% of HCV-1 patients, 18% of HCV-2/3 patients, and 21% of HCV-4 patients. In multivariate logistic regression analysis, baseline serum HCV RNA level > or =500,000 IU/mL (relative risk [RR] = 4.81, 95% confidence interval [CI]: 1.52 to 15.22; P = 0.008) and lack of rapid virologic response, defined as undetectable HCV RNA level at week 4 (RR = 2.94, 95% CI: 1.22 to 7.09; P = 0.02) were the best independent predictors of HCV relapse. Use of concomitant antiretroviral therapy also predicted relapse (P = 0.04), and a trend toward a higher relapse rate was recognized for HCV genotypes 1 and 4 versus genotypes 2 and 3 (P = 0.08). Extended treatment did not result in a lower incidence of relapse, at least for HCV genotypes 2 and 3. High baseline serum HCV RNA level and lack of undetectable viremia at week 4 are the most significant predictors of relapse in HCV/HIV-coinfected patients treated with peg-IFN plus weight-based RBV.

Peginterferon Alfa-2a and Ribavirin for 16 or 24 Weeks in HCV Genotype 2 or 3

Patients infected with hepatitis C virus (HCV) genotype 2 or 3 have sustained virologic response rates of approximately 80% after receiving treatment with peginterferon and ribavirin for 24 weeks. We conducted a large, randomized, multinational, noninferiority trial to determine whether similar efficacy could be achieved with only 16 weeks of treatment with peginterferon alfa-2a and ribavirin. We randomly assigned 1469 patients with HCV genotype 2 or 3 to receive 180 mug of peginterferon alfa-2a weekly, plus 800 mg of ribavirin daily, for either 16 or 24 weeks. A sustained virologic response was defined as an undetectable serum HCV RNA level (<50 IU per milliliter) 24 weeks after the end of treatment. The study failed to demonstrate that the 16-week regimen was noninferior to the 24-week regimen. The sustained virologic response rate was significantly lower in patients treated for 16 weeks than in patients treated for 24 weeks (62% vs. 70%; odds ratio for 16 weeks vs. 24 weeks, 0.67; 95% confidence interval, 0.54 to 0.84; P<0.001). In addition, the rate of relapse (a detectable HCV RNA level during follow-up in patients who had undetectable HCV RNA at the end of treatment) was significantly greater in the 16-week group (31%, vs. 18% in the 24-week group; P<0.001). The sustained virologic response rates in patients with a pretreatment serum HCV RNA level of 400,000 IU per milliliter or less was 82% with the 16-week regimen and 81% with the 24-week regimen. Among patients with a rapid virologic response (an undetectable HCV RNA level by week 4), sustained virologic response rates were 79% in the 16-week group and 85% in the 24-week group (P=0.02). Treatment with peginterferon and ribavirin for 16 weeks in patients infected with HCV genotype 2 or 3 results in a lower overall sustained virologic response rate than treatment with the standard 24-week regimen. (ClinicalTrials.gov number, NCT00077636 [ClinicalTrials.gov].).

Antinuclear antibody is associated with a more advanced fibrosis and lower RNA levels of hepatitis C virus in patients with chronic hepatitis C

Aims:Positive serum antinuclear antibody (ANA) is present in a number of patients with chronic hepatitis C virus (HCV) infection. This study aimed to evaluate the prevalence of ANA in patients...

Ultracentrifugation of Serum Samples Allows Detection of Hepatitis C Virus RNA in Patients with Occult Hepatitis C

Occult hepatitis C virus (HCV) infection of patients with abnormal liver function tests of unknown origin who are anti-HCV and serum HCV RNA negative but who have HCV RNA in the liver has been described. As HCV replicates in the liver cells of these patients, it could be that the amount of circulating viral particles is under the detection limit of the most sensitive techniques. To prove this hypothesis, serum samples from 106 patients with occult HCV infection were analyzed. Two milliliters of serum was ultracentrifuged over a 10% sucrose cushion for 17 h at 100,000 x g(av), where av means average, and HCV RNA detection was performed by strand-specific real-time PCR. Out of the 106 patients, 62 (58.5%) had detectable serum HCV RNA levels after ultracentrifugation, with a median load of 70.5 copies/ml (range, 18 to 192). Iodixanol density gradient studies revealed that HCV RNA was positive at densities of 1.03 to 1.04 and from 1.08 to 1.19 g/ml, which were very similar to those found in the sera of patients with classical chronic HCV infection. Antigenomic HCV RNA was found in the livers of 56 of 62 (90.3%) patients with detectable serum HCV RNA levels after ultracentrifugation, compared to 27 of 44 (61.4%) negative patients (P < 0.001). No differences in the median loads of antigenomic HCV RNA between patients with an those without serum HCV RNA (4.5 x 10(4) [range, 7.9 x 10(2) to 1.0 x 10(6)] versus 2.3 x 10(4) [range, 4.0 x 10(2) to 2.2 x 10(5)]) were found. Alanine aminotransferase and gamma-glutamyl transpeptidase levels, liver necroinflammatory activity, and fibrosis did not differ between both groups. In conclusion, HCV RNA can be detected in the sera of patients with occult HCV infection after circulating viral particles are concentrated by ultracentrifugation.

Utility of week-4 viral response to tailor treatment duration in hepatitis C virus genotype 3/HIV co-infected patients

To investigate the utility of a week-4 virological response for sustained response prediction in hepatitis C virus (HCV) genotype 3/HIV-co-infected patients treated with interferon and ribavirin for 24 weeks. Using a real-time polymerase chain reaction-based quantitative assay (COBAS AmpliPrep-COBAS-TaqMan 48; Roche Diagnostics) we retrospectively analysed samples obtained at baseline and weeks 4 and 12 from a subset of 35 HCV genotype 3-HIV co-infected patients enrolled in a randomized comparative trial of peginterferon alpha-2b versus interferon alpha-2b both in combination with ribavirin. In an intention-to-treat analysis, 78% of patients treated with peginterferon and 53% of those receiving standard interferon achieved a sustained virological response (SVR) Overall, at 4 weeks, 49% of patients had HCV RNA < 50 IU/ml and 63% had < 600 IU/ml. Of these rapid responders 88 and 86% achieved a SVR, respectively, with only one patient relapsing among end-of-treatment responders. In contrast, only 44 and 31% of patients with a week-4 HCV RNA >or= 50 or >or= 600 IU/ml achieved an SVR, respectively, with relapse rates of 33 and 50%, respectively. In multivariate logistic regression analysis a serum HCV RNA level below 600 IU/ml at week 4 was the strongest independent predictor of SVR (odds ratio, 11.3; 95% confidence interval, 1.7 to 75.0; P = 0.012). Monitoring early viral response may be useful to tailor the duration of treatment among patients with HCV genotype 3/HIV-co-infection. Patients whose HCV RNA falls below 600 IU/ml at 4 weeks are at low risk of relapse after 24 weeks of combination therapy.

Translation efficiencies of the 5′‐untranslated region of genotypes 1a and 3a in hepatitis C infected patients

Differences between the translation efficiencies mediated by the 5'-untranslated regions (5'-UTR) of genotypes (gt) 1 and 3 of hepatitis C virus (HCV) have been reported but it is unknown if such differences are biologically significant. The 5'-UTR was sequenced from paired serum and liver samples from 26 patients with chronic HCV hepatitis (11 gt 1a, 15 gt 3a). To determine whether there is a consistent difference between gts 1a and 3a translation efficiency, 5'-UTR (nt 1-356) and 5'-UTR plus core (nt 1-914) sequences were cloned into bicistronic, luciferase-encoding constructs and relative translation efficiencies (RTE) measured in Huh7 cells and BHK cells. The relationships between viral load, liver biopsy Ishak scores, degree of steatosis and translational activity of the patient-derived nucleotide sequence were examined. There were no differences in 5'-UTR sequence between serum and corresponding liver samples. The mean RTE of 5'-UTR sequences from gt 3a isolates was not significantly different from gt 1a whether or not the core encoding sequence was included, although inclusion of core led to a reduction in RTE by 93-97% for both genotypes. No correlation was found between RTE and serum HCV RNA levels, liver steatosis, inflammation, or fibrosis. However, a significant correlation was found between the presence of steatosis and infection with HCV gt 3a. It is concluded that there was no difference in translation efficiencies of 5'-UTRs from patients infected with gts 1a and 3a, and translation activity measured in vitro does not correlate with viral load or severity of liver disease.

Treatment of Hepatitis C in Hemodialysis Patients with Pegylated Interferon α-2a as Monotherapy

Background. The high prevalence of hepatitis C virus (HCV) infection in hemodialysis patients is of great concern because they have a higher rate of mortality than HCV-negative hemodialysis patients. The aim of the study was to evaluate the efficacy and safety of pegylated interferon α-2a monotherapy in hemodialysis patients with chronic HCV infection. Methods. Fourteen dialysis patients with chronic HCV infection were scheduled to receive 135 μg pegylated interferon α-2a subcutaneously, once a week, after dialysis session for a period of 48 weeks. Efficacy and safety were assessed by end of treatment viral response, sustained viral response, biochemical response, and adverse events. Serum HCV RNA levels were assessed using reverse transcriptase polymerase chain reaction (RT-PCR), while HCV genotype was analyzed by RT-PCR followed by hybridization of amplified products. Results. Of the 14 patients enrolled in the study, 9 completed treatment. Eight patients (57%) had undetectable levels of HCV RNA at the end of treatment, while one patient remained positive. Two (14.3%) patients were discontinued because of insufficient therapeutic response. Three patients (21.34%) did not finish treatment because serious adverse events occurred: one patient with bronchopneumonia and one with pericarditis were discontinued from treatment, while one patient died due to cerebral hemorrhage. Sustained viral response was present in 36% of the patients (5/8 patients) at the end of the follow up period. Biochemical response with normalization of serum ALT levels during treatment was observed in all treated patients (83 ± 20.1 U/L at baseline vs. 23.4 ± 4.6 U/L at week 48). The most common adverse events were flu-like syndrome, myalgia, arthralgia, and pancytopenia. Most of the adverse events were manageable. The serious adverse events were believed to be unrelated to the therapy, but rather to the co-morbidities of the hemodialysis patients. Conclusions. Pegylated interferon α-2a treatment was effective in a considerable proportion of the treated hemodialysis patients with hepatitis C, and it was reasonably safe to use.

Clinical Outcome after Living Donor Liver Transplantation in Patients with Hepatitis C Virus-associated Cirrhosis

Hepatitis C virus (HCV)-associated cirrhosis is an increasingly frequent indication for liver transplantation (LT). However, HCV recurrence is universal and this immediately occurs following LT, which endangers both the graft and patient survival. We investigated the frequency of posttransplant recurrence of HCV infection and the patient-graft survival, and we analyzed the responses to ribavirin and interferon therapy in the patients with recurrent HCV infection after living donor liver transplantation (LDLT). We retrospectively reviewed the clinical outcomes of 39 HCV-associated cirrhosis patients who underwent LDLT at Asan Medical Center between August 1992 and June 2006. In this study, the diagnosis of recurrent HCV was made on the basis of increased transaminases and serum HCV RNA levels greater than 10 million IU/mL because protocol liver biopsy was not performed. HCV recurrence was seen in 26 of the 39 LDLT patients (66.7%). 86.7% of recurrence occurred within the first postoperative year. Antiviral treatment was used for all patients with recurrence of HCV. None of the 10 patients receiving ribavirin alone and 9 of 16 patients who received combination therapy with pegylated interferon alpha-2a plus ribavirin became HCV RNA negative and they remained persistently negative during the median follow-up of 24.9 months. Our data indicates that there is no significant factor influencing HCV recurrence except for the recipient's age. The 2-year patient survival for the HCV patients with HCC and those patients without HCC were 81.2% and 81.3%, respectively (P=0.85) and the 2-year graft survival rates were 81.2% and 68.2%, respectively (P=0.29). No patient died from HCV recurrence during the follow-up period. Combination therapy with ribavirin and interferon appears to improve the outcome of recurrent HCV infected patients after LDLT.

Interferon and ribavirin treatment results of patients with HBV–HCV co-infection cured of childhood malignancies

We aimed to investigate the virological and clinical characteristics and the results of combination therapy in six oncology patients with hepatitis B virus (HBV)-hepatitis C virus (HCV) co-infection. Six patients (five male and one female; age range 8-14 years), diagnosed with HBV-HCV infections during follow-up at the oncology outpatient clinic during 2000-2001 were included in the study. They had received an average of 25.8 units of blood by transfusion per patient during their treatment for malignancies. Positive serological HBV indicators were determined 20-40 months after the end of chemotherapy. HCV RNA positivity was determined together with HBV at an average of 3.3 months after hepatitis B infection. Patients received interferon-alpha-2b and ribavirin for 12 months. Both HBV DNA and HCV RNA became negative, and anti-HBe became positive in one patient. One patient had decreased HBV DNA levels and negative HCV RNA and HBeAg, but HBeAg became positive again at 18-months following treatment. Another patient had decreased serum HBV DNA and HCV RNA levels with normal ALT levels at the end of treatment; however, two months after therapy was ceased these values returned to pretreatment levels. We observed that combined treatment is effective in HBV-HCV infection. The effectiveness of combined treatment should be researched with larger groups of co-infected patients.

Randomized, double‐blind, placebo‐controlled trial of bovine lactoferrin in patients with chronic hepatitis C

Several studies have suggested that lactoferrin administration may decrease the serum level of hepatitis C virus (HCV) RNA in patients with chronic hepatitis C. The aim of the present study was to confirm the efficacy of orally administered bovine lactoferrin (bLF) in patients with chronic hepatitis C. The patients with chronic hepatitis C randomly received either oral bLF at a dose of 1.8 g daily for 12 weeks, or an oral placebo. The primary endpoint was the virologic response, defined as a 50% or greater decrease in serum HCV RNA level at 12 weeks compared with the baseline. The secondary endpoint was the biochemical response, which was defined as a 50% or greater decrease in the serum alanine aminotransferase (ALT) level at 12 weeks compared with the baseline. One hundred and ninety-eight of 199 patients were evaluable for efficacy and safety. bLF treatment was well tolerated and no serious toxicities were observed. A virologic response was achieved in 14 of 97 patients (14.4%) in the bLF group, and 19 of 101 (18.8%) in the placebo group. There was no significant difference in virologic response rates between the two groups (-4.4%, 95% confidence interval -14.8, 6.1). In addition, bLF intake did not have any favorable effect on the serum ALT level. The virologic responses were not different between two groups in any subgroup analysis. In conclusion, orally administered bLF does not demonstrate any significant efficacy in patients with chronic hepatitis C.

Distribution of HCV Genotypes in Patients with End-Stage Renal Disease According to Type of Dialysis Treatment

The objective of this study was to investigate the effects of types of dialysis treatments on hepatitis C virus infection and the epidemiologic properties of hepatitis C virus (HCV) infection at three Baskent University hospitals, in Ankara, Adana, and Izmir, Turkey, in 655, 326, and 118 patients with end-stage renal disease, respectively. One hundred thirty patients with HCV viremia among 271 patients with end-stage renal disease seropositive for HCV were included in this cross-sectional study. HCV RNA-positive patients were classified according to the renal replacement therapies (hemodialysis or continuous ambulatory peritoneal dialysis), and viral load, transaminase levels, and distribution of genotypes were compared between these subgroups. In the continuous ambulatory peritoneal dialysis group, 26 of 165 patients (16%) were serum anti-HCV positive, and 11 of 26 patients (42%) were serum HCV RNA positive. Twenty-six percent of the patients undergoing hemodialysis were anti-HCV positive, and 49% were HCV RNA positive. The prevalence of genotype 1b was 68% and 73% for patients in the continuous ambulatory peritoneal dialysis and hemodialysis groups, respectively. No significant differences were found between the genotype 1b and the non-1b groups or between different dialysis types with regard to age and sex and serum aspartate transaminase, alanine aminotransferase, and HCV RNA levels. We conclude that HCV seropositivity may differ between different types of dialysis treatments, although viral load and genotypes may be similar in persons with end-stage renal disease and those without.

Serine palmitoyltransferase inhibitor suppresses HCV replication in a mouse model

Serine palmitoyltransferase (SPT) is a first-step enzyme in the sphingolipid biosynthetic pathway. Myriocin is an inhibitor of SPT and suppresses replication of the hepatitis C virus (HCV) replicon. However, it is still unknown whether this SPT inhibitor suppresses HCV replication in vivo. We investigated the anti-HCV effect of myriocin against intact HCV using chimeric mice with humanized liver infected with HCV genotype 1a or 1b. We administered myriocin into HCV infected chimeric mice and succeeded in reducing the HCV RNA levels in serum and liver to 1/10–1/100 of the levels prior to the 8 day treatment. Furthermore, combined treatment with pegylated interferon reduced the HCV RNA levels to less than 1/1000 of the control levels. We strongly suggest that suppression of SPT reduces HCV replication, and therefore that the SPT inhibitor is potentially a novel drug in the treatment of HCV infection.

Chronic Hepatitis C in Patients With Persistently Normal Alanine Transaminase Levels

Many patients with chronic hepatitis C virus (HCV) have persistently normal serum alanine transaminase (ALT) levels. We compared characteristics of chronic hepatitis C patients with patients with normal and elevated ALT levels using data from 3 randomized phase III trials of peginterferon alfa-2a (40 kDa). The characteristics of 480 patients with normal ALT values (on >or=3 occasions without any increases in ALT level over a 6- to 18-month period) and 1993 patients with elevated ALT levels were compared. Sixty-eight of the 480 patients with normal ALT levels were randomized to no treatment and monitored for 72 weeks. More patients with normal ALT levels than patients with elevated ALT levels were women (59% vs 32%; P<.01). The serum HCV RNA titer was significantly lower in patients with normal ALT levels (P<.01 vs in patients with elevated ALT levels). Patients with normal ALT levels had significantly lower inflammation and fibrosis scores on liver biopsy examination than patients with elevated ALT levels, but almost two-thirds had portal fibrosis and 10% had bridging fibrosis. No correlation between baseline ALT activity, HCV RNA level, and liver histology was observed in patients with normal ALT levels. During the 72-week follow-up period, ALT activity elevated above the upper limit of normal in 53% of the untreated patients with normal levels of ALT. None became HCV RNA undetectable. Chronic hepatitis C patients with normal ALT levels should be evaluated in a similar manner as patients with elevated ALT levels because they are at risk for developing significant liver disease. The decision to treat with peginterferon alfa and ribavirin should be based on multiple factors, rather than on ALT levels alone.

Predictors of Hepatitis C Virus RNA Levels in a Prospective Cohort Study of Drug Users

High levels of hepatitis C virus (HCV) RNA are associated with a poor response to treatment of chronic hepatitis C, and a substantial reduction in HCV RNA levels predicts a favorable treatment response. We prospectively studied time-dependent and time-independent predictors of HCV RNA levels in 264 drug users with chronic HCV infection. Interviews on medical history and high-risk behaviors, phlebotomy for HIV viral load, serum HCV RNA levels as measured by the COBAS Amplicor HCV Monitor (Roche Diagnostics, Branchburg, NJ), and a lymphocyte subset assay were performed. Factors associated with HCV RNA levels over time were analyzed using a linear mixed model. Nearly 70% of the participants were men, two thirds were Hispanic, and the mean age was 46 years. HCV RNA levels increased over time. Older age (P < 0.001), HIV seropositivity (P = 0.03), and HCV nongenotype 1 (P = 0.05) were predictors of higher HCV RNA levels on multivariate analysis. Among 142 HIV-seropositive participants, a detectable HIV-1 viral load (P < 0.001) and recent alcohol use (P = 0.02) were predictors of higher HCV RNA levels. The predictors of higher HCV RNA levels found in this longitudinal study are consistent with those of prior cross-sectional studies. Further studies are warranted to determine if treatment of alcohol use affects HCV RNA levels.

Hepatitis C Virus–Specific Immune Responses and Quasi‐Species Variability at Baseline Are Associated with Nonresponse to Antiviral Therapy during Advanced Hepatitis C

Pretreatment hepatitis C virus (HCV)-specific lymphoproliferative (LP) responses, neutralizing antibody (NA) responses, intrahepatic cytotoxic T lymphocyte (CTL) responses, and HCV quasi-species (QS) diversity and complexity were examined in patients with advanced hepatic fibrosis (Ishak fibrosis score of > or = 3) and prior nonresponse to interferon (IFN)- alpha therapy who were enrolled in the initial phase of the Hepatitis C Antiviral Long-Term Treatment against Cirrhosis Trial. Positive baseline HCV E1- and/or E2-specific NA responses (P = .01) and higher baseline HCV QS diversity (P = .01) were more commonly found in patients who did not become sustained virologic responders (SVRs) at week 72 (W72) than they were in those who did. No patients with positive results for both the LP and NA assays achieved a sustained virologic response. Multiple logistic regression analysis revealed that, when the presence of cirrhosis, prior ribavirin therapy, genotype 1 infection, log serum HCV RNA level, and receipt of >80% of the prescribed medication were controlled for, a sustained virologic response (W72) was negatively correlated with positive baseline LP assay results (P = .02) and with 1 or more positive assays (LP, NA, or CTL) (P = .02). No differences were noted in baseline intrahepatic CTL activity between SVRs and non-SVRs. Thus, in patients with advanced hepatic fibrosis due to HCV infection, pretreatment HCV-specific immune responses and increased QS variability appear to hinder viral clearance by pegylated IFN- alpha 2a and ribavirin combination therapy.

Predictors of Liver Fibrosis in HIV-Infected Patients with Chronic Hepatitis C Virus (HCV) Infection: Assessment Using Transient Elastometry and the Role of HCV Genotype 3

Liver fibrosis is accelerated in patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV). The reasons for this faster liver disease progression are unclear, although higher plasma HCV RNA levels and distinct HCV genotype distribution in this population, compared with in HCV-monoinfected subjects, could play a role. Liver fibrosis was assessed using elastometry in all consecutive HIV-infected patients with chronic hepatitis C who attended our institution (Hospital Carlos III, Madrid) during the past 12 months. Hepatic stiffness was measured in kiloPascal units (kPa) and was interpreted on the basis of Metavir score: no or mild fibrosis (score, F0-F1) when liver stiffness is < or =7.1 kPa, and fibrosis with septa or cirrhosis (F2-F4) when >7.1 kPa. A total of 283 patients (71% were male; mean age, 42 years; 94% were injection drug users and 94% were receiving antiretrovirals; mean CD4 cell count, 554 cells/microL; 72% with plasma HIV RNA level of <50 copies/mL) were analyzed. The mean alanine aminotransferase level was 68 IU/L, and the mean plasma HCV RNA level was 5.9 log IU/mL. HCV genotype distribution was as follows: genotype 1, 60% of patients; genotype 2, 2%; genotype 3, 26%; and genotype 4, 12%. Overall, 164 (58%) of the patients had scores indicating advanced liver fibrosis (F2-F4), as determined using elastometry. In the univariate and multivariate analyses, respectively, a significant odds ratio (OR) for score F2-F4 was found for HCV genotype 3, compared with the other genotypes (OR, 1.9 [95% confidence interval {CI}, 1.1-3.4] vs. 4.3 [95% CI, 1.4-13.3]); for older age (OR, 1.1 [95% CI, 1.03-1.17] vs. 1.1 [95% CI, 1.01-1.25]); and for elevated alanine aminotransferase levels (OR, 1.02 [95% CI, 1.01-1.03] vs. 1.03 [95% CI, 1.01-1.04]). Although patients with HCV genotype 1 had higher mean serum HCV RNA levels than did those with HCV genotype 3 (6.1 log IU/mL vs. 5.7 log IU/mL; P=.01), patients with HCV genotype 3 tended to have F2-F4 scores more frequently than did those with HCV genotype 1 (69% vs. 58%; P = not significant). HCV genotype 3, older age, and elevated alanine aminotransferase levels are independent predictors of advanced liver fibrosis in HCV-HIV-coinfected patients.